A treatment for major depression that rapidly resulted in full symptomatic remission for increased numbers of patients would be a significant clinical advance. Continuing impairment has been attributed not only to nonresponse, but also to improvement without full remission. Most previous research has assumed a several week lag before antidepressants work, attributable to mechanistic delays translating immediate drug actions into mood and behavioral effects. Additional delays in prescribing maximal dose and in ultimately prescribing effective treatment if initial therapy is ineffective also increase time to remission. Eliminating these delays would be a major public health boon. This two-site, randomized, double-blind study of 240 patients with DSM-IV Major Depressive Disorder will test whether combining escitalopram (ESC) and buproprion (BUP) accelerates response and increases the proportion in full remission. ESC + BUP (N=80) will be contrasted with ESC+ placebo (N=80), and separately with BUP+placebo (N=80). Six months follow-up will assess durability and costs. This study is based on both translational application of pre-clinical synergy between ESC and BUP, and on preliminary clinical data demonstrating rapid remission of major depression in 40 patients treated with ESC + BUP. In rat dorsal raphe, a marked increase in 5-HT neuronal firing was demonstrated to be superior to the mild synergistic effect. In humans, ESC + BUP resulted in both rapid remission (34% in the 1st two weeks) and increased final remission (62% at end of treatment). We conceptualize this study as the first in a series. If this study demonstrates an advantage for ESC + BUP, subsequent studies would replicate the rapid onset and greater overall effectiveness of ESC + BUP, document its long-term safety, durability and portability, investigate its utility relative to other dual therapies and the need for rapid dosing. Positive outcomes would argue for a major change in clinical practice with resultant marked decrease in depression's morbidity. Finally, this clinical finding could stimulate further preclinical work to develop better norepinephrine releasing agents or inhibitors of 5-HT1A autoreceptors and to investigate the interactive role of norepinephrine and 5-HT1A autoreceptors in the pathophysiology of Major Depressive Disorder and its treatment.